The brain is an extremely complex circuit. For example, a single neuron can receive over 10,000 synaptic inputs and express multiple neurotransmitter receptor types that must be segregated to appropriate synaptic sites. While complex, the nervous system also must remain malleable. Understanding how the nervous system forms synapses and regulates their composition is key to understanding the basis for learning and memory.

Our work is focused on two primary questions. First, how are different receptor types sorted to the appropriate synapses in a neuron? Second, how do synapses in the central nervous system change in the growing animal? We have taken advantage of the simple anatomy and well-characterized genetics of C. elegans to address these questions. By using genetic screens, behavioral analysis, and molecular and cell biological techniques in living animals, we hope to identify the proteins that build and regulate synapses.

Previously, we have shown that the PDZ-domain containing protein LIN-10 is required for the localization of GLR-1, an AMPA-class neurotransmitter receptor subunit, to synapses. We would like to understand how LIN-10 functions to localize the GLR-1 receptor to synapses between neurons. Current experiments aim to identify other proteins that, in cooperation with LIN-10, localize glutamate receptors.

We have shown that glutamatergic synapse number increases four fold during C. elegans larval development. This increase reflects a coupling between body size and synapse number that maintains a constant density of synapses along the neuropil. Our genetic analysis has shown that UNC-43, the worm CaM Kinase II, is required to regulate synapse number during growth by mobilizing intracellular pools of neurotransmitter receptor to form new synapses. Current experiments aim to understand how CaMKII modifies synaptic connections in response to changes in body size. An understanding of this mechanism will require the identification of the targets of the kinase and the effect that phosphorylation has upon these targets.

We have also found that CaMKII is localized to synaptic sites. and that upon constitutive activation of CaMKII in response to high calcium levels. CaMKII delocalizes from synaptic sites so that it can no longer maintain GLR-1 at these sites. Current experiments aim to understand how CaMKII is localized to synapses, and how this localization is regulated by phosphorylation of the kinase in response to calcium influx. An understanding of this mechanism will require the identification of proteins that bind and/or localize the kinase to synapses.